Asparagine synthetase deficiency

Description

Asparagine synthetase deficiency is a condition that causes neurological problems in affected individuals starting soon after birth. Most people with this condition have an unusually small head size (microcephaly) that worsens over time due to loss (atrophy) of brain tissue. They also have severe developmental delay that affects both mental and motor skills (psychomotor delay). Affected individuals cannot sit, crawl, or walk and are unable to communicate verbally or nonverbally. The few affected children who achieve developmental milestones often lose these skills over time (developmental regression).

Most individuals with asparagine synthetase deficiency have exaggerated reflexes ( hyperreflexia) and weak muscle tone (hypotonia). The muscle problems worsen through childhood and lead to muscle stiffness, uncontrolled movements, and ultimately, paralysis of the arms and legs (spastic quadriplegia). Many affected individuals also have recurrent seizures (epilepsy). Not all affected people experience the same type of seizure. The most common types involve a loss of consciousness, muscle rigidity, and convulsions (tonic-clonic); involuntary muscle twitches (myoclonic); or abnormal muscle contraction (tonic). People with asparagine synthetase deficiency may have an exaggerated startle reaction (hyperekplexia) to unexpected stimuli. Some affected individuals have blindness due to impairment of the area of the brain responsible for processing vision, called the occipital cortex (cortical blindness).

People with asparagine synthetase deficiency typically do not survive past childhood.

Frequency

Asparagine synthetase deficiency is thought to be a rare condition. More than 20 affected individuals have been described in the medical literature.

Causes

Asparagine synthetase deficiency is caused by mutations in a gene called ASNS. This gene provides instructions for making an called asparagine synthetase. This enzyme is found in cells throughout the body, where it converts the protein building block () to the amino acid asparagine.

In addition to being a component of proteins, asparagine helps to break down toxic within cells, is important for protein modification, and is needed for making a

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 1 molecule that transmits signals in the brain (a neurotransmitter). Mutations in the ASNS gene that cause asparagine synthetase deficiency lead to a decrease or loss of functional enzyme. Asparagine from the diet likely makes up for the enzyme's inability to produce the amino acid in most cells. However, asparagine cannot cross the protective barrier that allows only certain substances to pass between blood vessels and the brain ( the blood-brain barrier). As a result, brain cells in people with asparagine synthetase deficiency have a shortage (deficiency) of this amino acid. The exact effect of asparagine synthetase deficiency on brain cells is unknown, but because of the severe features of this condition, it is clear that asparagine is necessary for normal brain development.

Learn more about the gene associated with Asparagine synthetase deficiency

• ASNS

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• ASNS deficiency • ASNSD • Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome • Disorder of asparagine

Additional Information & Resources

Genetic Testing Information

• Genetic Testing Registry: Asparagine synthetase deficiency (https://www.ncbi.nlm.n ih.gov/gtr/conditions/C3809971/)

Patient Support and Advocacy Resources

• Disease InfoSearch (https://www.diseaseinfosearch.org/) • National Organization for Rare Disorders (NORD) (https://rarediseases.org/)

Research Studies from ClinicalTrials.gov

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 2

• ClinicalTrials.gov (https://clinicaltrials.gov/ct2/results?cond=%22asparagine+synthet ase+deficiency%22)

Catalog of Genes and Diseases from OMIM

• ASPARAGINE SYNTHETASE DEFICIENCY (https://omim.org/entry/615574)

Scientific Articles on PubMed

• PubMed (https://pubmed.ncbi.nlm.nih.gov/?term=%28%28asparagine+synthetase% 5BTIAB%5D%29+AND+%28deficiency%5BTIAB%5D%29%29+AND+english%5Bla %5D+AND+human%5Bmh%5D+AND+%22last+3600+days%22%5Bdp%5D)

References

• Alfadhel M, Alrifai MT, Trujillano D, Alshaalan H, Al Othaim A, Al Rasheed S, Assiri H, Alqahtani AA, Alaamery M, Rolfs A, Eyaid W. Asparagine SynthetaseDeficiency: New Inborn Errors of Metabolism. JIMD Rep. 2015;22:11-6. doi:10.1007/8904_2014_ 405. Epub 2015 Feb 8. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/25663 424) or Free article on PubMed Central (https://www.ncbi.nlm.nih.gov/pmc/articles/P MC4486270/) • Lomelino CL, Andring JT, McKenna R, Kilberg MS. Asparagine synthetase:Function, structure, and role in disease. J Biol Chem. 2017 Dec8;292(49):19952-19958. doi: 10.1074/jbc.R117.819060. Epub 2017 Oct 30. Review. Citation on PubMed (https://p ubmed.ncbi.nlm.nih.gov/29084849) or Free article on PubMed Central (https://www. ncbi.nlm.nih.gov/pmc/articles/PMC5723983/) • Palmer EE, Hayner J, Sachdev R, Cardamone M, Kandula T, Morris P, Dias KR, TaoJ, Miller D, Zhu Y, Macintosh R, Dinger ME, Cowley MJ, Buckley MF, Roscioli T, Bye A, Kilberg MS, Kirk EP. Asparagine Synthetase Deficiency causes reducedproliferation of cells under conditions of limited asparagine. Mol Genet Metab.2015 Nov;116(3):178-86. doi: 10.1016/j.ymgme.2015.08.007. Epub 2015 Aug 14. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/26318253) • Ruzzo EK, Capo-Chichi JM, Ben-Zeev B, Chitayat D, Mao H, Pappas AL, Hitomi Y, Lu YF, Yao X, Hamdan FF, Pelak K, Reznik-Wolf H, Bar-Joseph I, Oz-Levi D, Lev D, Lerman-Sagie T, Leshinsky-Silver E, Anikster Y, Ben-Asher E, Olender T, Colleaux L, Décarie JC, Blaser S, Banwell B, Joshi RB, He XP, Patry L, Silver RJ, Dobrzeniecka S, Islam MS, Hasnat A, Samuels ME, Aryal DK, Rodriguiz RM, Jiang YH,Wetsel WC, McNamara JO, Rouleau GA, Silver DL, Lancet D, Pras E, Mitchell GA,Michaud JL, Goldstein DB. Deficiency of asparagine synthetase causes congenitalmicrocephaly and a progressive form of encephalopathy. Neuron. 2013 Oct16;80(2):429-41. doi: 10.1016/j.neuron.2013.08.013. Citation on PubMed (https:// pubmed.ncbi.nlm.nih.gov/24139043) or Free article on PubMed Central (https://www .ncbi.nlm.nih.gov/pmc/articles/PMC3820368/)

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 3 • Sacharow SJ, Dudenhausen EE, Lomelino CL, Rodan L, El Achkar CM, Olson HE, Genetti CA, Agrawal PB, McKenna R, Kilberg MS. Characterization of a novelvariant in siblings with Asparagine Synthetase Deficiency. Mol Genet Metab. 2018 Mar;123( 3):317-325. doi: 10.1016/j.ymgme.2017.12.433. Epub 2017 Dec 20. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/29279279) or Free article on PubMed Central (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832599/)

Page last updated on 18 August 2020

Page last reviewed: 1 November 2018

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 4